19-nortestosterone Derivatives Research Articles

Dienogest versus gonadotropin-releasing hormone analogues for the clinical treatment of endometriosis: an updated meta-analysis

Endometriosis is a chronic gynecological condition where endometrial-like tissue grows outside the uterus, leading to persistent pelvic pain, dysmenorrhea, dyspareunia, and infertility. The objective of the systematic review was to examine the efficacy and safety of Dienogest, which is a synthetic, orally active 19-nortestosterone derivative, in the treatment of women with endometriosis compared to GnRH-a, which is commonly used to treat conditions like endometriosis. We conducted a search of PubMed, Google Scholar, and Cochrane Library databases from inception until August 2024 for clinical studies, using the following keywords: ("Dienogest") and ("gonadotropin-releasing hormone analogue" or GnRH Analogues OR GnRH agonist) and (Endometriosis). Relevant randomized control trials were identified. Pooled effect estimates were calculated using a random effect model. This meta-analysis included eight randomized controlled trials (RCTs) with 1,219 patients, 602 in the dienogest group and 617 in the GnRH analogue group. Both treatments were equally effective in controlling pain, dysmenorrhea, and dyspareunia, but dienogest offered advantages. Dienogest significantly reduced the recurrence rate (RR: 0.37, 95% CI [0.15, 0.91]; p=0.03) and hot flushes (RR: 0.24, 95% CI [0.10, 0.59]; p=0.002) and protected against bone mineral density (BMD) loss. However, it increased the risk of irregular vaginal bleeding (RR: 3.61, 95% CI [1.09, 11.97]; p=0.04). Other side effects, such as headache, vaginal dryness, spotting, and alopecia, were not statistically significant. It concluded that Dienogest has comparatively fewer side effects than GnRH analogue, making it a considerably safer option for treating endometriosis.

Progestins as a Contributing Factor to Hepatocellular Adenoma: A Case Series and Literature Review

Study objectiveTo explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA). MethodsWe describe three cases of adolescents and young adults who developed HA while on norethindrone (NET), and their management. In addition, we provide a comprehensive literature review on the association of progestins and HA. ResultsSince 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on norethindrone (NET), and five on a prodrug of norethindrone (four on norethindrone acetate (NETA) and one on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: four experienced a size reduction and three had complete resolution of their HA. Among our patients, one ceased NET and instead had a levonorgestrel intrauterine device inserted and another swapped from NET to oral medroxyprogesterone acetate: both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. ConclusionThese cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared to the levonorgestrel-IUD. There are no case reports relating to other forms of progestins such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities.

Estro-progestin and progestogen intake: What's the impact on hysteroscopic imaging?

In current literature there is no report aimed to evaluate the effects of exogenous steroids on hysteroscopic imaging. To evaluate the hysteroscopic features of endometrium in women undergoing female hormones administration. We reviewed video-records of hysteroscopies carried-out in women taking estro-progestins (EP), progestogen (P) and Hormonal Replacement Therapy (HRT). All women underwent biopsies resulting in atrophic, functional, or dysfunctional pathological reports. Description of hysteroscopic pictures related to each schedule of therapy. The study included 117 women. We evaluated 82, 24 and 11 women treated by EP, P and HRT, respectively. In EP users, imaging indistinguishable from physiological pictures was found when high oestrogen dosage and low-potency progestogen as 17-OH progesterone derivatives were administered. By enhancing progestogen potency with 19-norprogesterone and 19-nortestosterone derivatives we observed a promotion of progestogen differentiation such as polypoid-papillary pseudo-decidualisation, spiral artery differentiation, inhibition of gland-proliferation and endometrial atrophy. In P users we distinguished two patterns, depending on continuous or sequential schedules. Continuous therapy resulted in atrophic or proliferative-secretory features whereas sequential ones led to endometrial overgrowth reflecting stromal pseudo-decidualisation. Women undergoing HRT showed atrophic features in combined continuous and polypoid overgrowth in sequential schedules. In women taking Tibolone we found pictures ranging from atrophic to hyperplastic appearances. Exogenous steroids lead to significant endometrial moulding. Depending on schedule, hysteroscopic-view appears predictable and often showing overgrowths mimicking proliferative pathologies. In this case biopsy is recommended but in common practice physicians should gain awareness with hysteroscopic pictures induced from hormone administration. Systematic assessment of hysteroscopic pictures during estro-progestins intake.

Fate and behavior of progestogens in activated sludge treatment: Kinetics and transformation products

Previous studies have shown the high ecotoxicological potential of progestogens (PGs) on the reproductive system of aquatic organisms. Yet the ubiquitous presence of several PGs in wastewater treatment plant (WWTP) effluents indicates an incomplete removal during treatment. To investigate the fate and behavior of PGs during biological wastewater treatment, nine commonly used PGs were incubated in aerobic lab-scale degradation experiments with activated sludge taken from a municipal WWTP. The degradation kinetics revealed a fast removal after 48 h for most of the compounds. Cyproterone acetate and dienogest were the most recalcitrant of the analyzed steroids with half-lives of 8.65 h and 4.55 h, respectively. Thus, only moderate removals of these PGs can be predicted in full-scale WWTPs. Moreover, numerous transformation products (TPs) were detected via high-resolution mass spectrometry. Hydrogenation or dehydrogenation of ring A and non-selective hydroxylations of 17α-hydroxyprogesterone derivatives (medroxyprogesterone acetate, chlormadinone acetate, cyproterone acetate) as well as for 19-nortestosterone derivatives (dienogest, norethisterone acetate, etonogestrel) were observed as major transformation reactions. Seven of the identified TPs were confirmed by reference standards. The biodegradation of cyproterone acetate revealed an almost quantitative transformation to 3α‑hydroxy cyproterone acetate which is reported to be genotoxic. In a comparative evaluation of the TPs formed and the steroid structure, it was observed that molecular structure played a role in the inhibition of several transformation reactions, explaining the increased recalcitrance of these compounds. In addition, aromatization of the steroid ring A was identified for the 19-nortestosterone derivatives leading to the formation of estrogen-like TPs. For instance, the degradation of norethisterone acetate led to the formation of 17α-ethinylestradiol, a well-known and very potent synthetic estrogen. The evidence of the conversion of progestogenic to estrogenic compounds and the formation of potentially hazardous TPs indicates the need of a more comprehensive environmental risk assessment for synthetic steroids. Two of the newly identified TPs (3α-hydroxy cyproterone acetate and ∆9,11-dehydro-17α-cyanomethyl estradiol) were detected in WWTP effluents for the first time.

Safety of Dienogest and Other Hormonal Treatments for Endometriosis in Real-World Clinical Practice (VIPOS): A Large Noninterventional Study.

IntroductionEndometriosis is a common gynecologic disease associated with a significant burden on women’s health and healthcare systems. Currently approved hormonal treatments for endometriosis can be effective in controlling symptoms, but may have clinically relevant side effects that limit their long-term use. Dienogest 2 mg (Visanne; Bayer AG, Berlin, Germany) is a 19-nortestosterone derivative that significantly reduces menstrual bleeding, dysmenorrhea, premenstrual pain, dyspareunia, and pelvic pain in women with endometriosis. Although dienogest 2 mg has demonstrated efficacy in clinical trials, data regarding long-term and real-world use are limited.MethodsTo our knowledge, the Visanne Post-approval Observational Study (VIPOS) is the largest real-world, noninterventional study performed examining the safety of dienogest and other hormonal treatments for the management of endometriosis in routine clinical practice. Patients self-reported medical and gynecologic history and symptoms and treatment information. Primary clinical outcomes were clinically validated and subject to independent blinded adjudication. Loss to follow-up was minimized through active contact with participating women at 6 months post-enrollment and annually thereafter to ensure almost all clinically relevant outcomes were captured.Planned OutcomesVIPOS planned to enroll approximately 25,000 women initiating a new treatment for endometriosis, including those prescribed dienogest 2 mg/day and other hormonal medications for endometriosis (approved or nonapproved), from approximately 1000 centers in six European countries. The main clinical outcomes of interest for follow-up are anemia requiring medical intervention, de novo or clinically worsening depression, and treatment-failure patterns that result in drug discontinuation. Additional analyses will characterize the baseline risk factors of medically managed patients with endometriosis and assess treatment utilization patterns. VIPOS was designed to provide real-world information on endometriosis treatment and associated clinical outcomes, while not affecting the prescribing physician’s decisions or the classification of patient diagnoses.Trial RegistrationEuropean Union Electronic Register of Post-Authorisation Studies (EU PAS) no. 1613, Clinicaltrials.gov: NCT01266421.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01331-z) contains supplementary material, which is available to authorized users.

Occurrence and mass balance of sixty-two progestins in a municipal sewage treatment plant

Progestins (PGs) are a group of steroid hormones known to have endocrine-disrupting effects. These compounds can enter the aquatic environment via the discharge of treated or untreated wastewater and the disposal of sludge from sewage treatment plants (STPs); thus, their removal in STPs are of great importance. The present study simultaneously investigated the occurrences and fates of 62 PGs in a municipal STP in Beijing, China. Progesterone (P) and its metabolites were found to be the predominant compounds, with total dissolved concentrations of 1866 ng/L in the influent. About 11 P metabolites were newly detected, accounting for 25–55% and 75–91% of the total concentrations in wastewater and sludge, respectively. For the other three groups of PGs derived from different parent compounds, P derivatives were first detected in the STP with the highest concentration in the wastewater and sludge, followed by 19-nortestosterone (NT) derivatives and 17α-hydroxyprogesterone (17α-OHP) derivatives. The removal efficiencies in the dissolved phase of wastewater were relatively high for P and its metabolites (95–99%) and P derivatives (91–99%). And the relative persistence of NT (68–99%) and 17α-OHP derivatives (79–99%) was observed during the wastewater treatment processes. Mass balance analysis showed that the lost mass proportions were as high as 41–99%, the mass fractions in sludge were in the range of 0–55%, and 0.24–25% of the initial mass loadings was present in the effluent. These results indicated that biodegradation was the major removal mechanism of PGs in the STP.

Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

19-Nortestosterone C-17 epimers with prominent antiproliferative properties have been previously described. In our present study, five novel 17α-19-nortestosterones (3−7) were synthesized to increase their beneficial biological activities with no associated undesired hormonal effects. The compounds were screened by a viability assay against a panel of human adherent gynecological cancer cell lines. Three of the tested derivatives (3−5) exhibited a remarkable inhibitory effect on the proliferation of HeLa cells with IC50 values lower than that of our reference agent cisplatin (CIS). These three active agents also displayed considerable cancer selectivity as evidenced by their weaker growth inhibitory effect on non-cancerous fibroblast cells compared to CIS. The most potent newly synthesized 17α-chloro derivative (3) was selected for additional experiments in order to characterize its mechanism of action. Since nandrolone (19-nortestosterone, 1) is a structural analog with selective antiproliferative action on cervical carcinoma cells, it was utilized as a positive control in these studies. A lactate dehydrogenase (LDH) assay demonstrated a moderate cytotoxic effect of the test compounds. Cell cycle disturbance and the elevation of the hypodiploid population elicited by the test agents were detected by flow cytometry following propidium staining. The proapoptotic effects of the tested steroids were confirmed by fluorescent microscopy and a caspase-3 activity assay. Treatment-related caspase-9 activation without a substantial change in caspase-8 activity indicates the induction of the intrinsic apoptotic pathway. The selected agents directly influence the rate of tubulin assembly as evidenced by a polymerization assay. Yeast-based reporter gene assay revealed that the androgenic activity of the novel 19-nortestosterone derivative 3 is by multiple orders of magnitude weaker than that of the reference agent 1. Based on the behavior of the examined compounds it can be concluded that a halogen substitution of the 19-nortestosterone scaffold at the 17α position may produce compounds with unique biological activities. The results of the present study support that structurally modified steroids with negligible hormonal activity are a promising basis for the research and development of novel anticancer agents.

Trace analysis of 61 natural and synthetic progestins in river water and sewage effluents by ultra-high performance liquid chromatography–tandem mass spectrometry

A broad number of natural and synthetic progestins are widely used in human and veterinary therapies. Although progestins exhibit adverse effects in aquatic organisms, information about environmental occurrence and fate have been limited to several compounds, hampering the accuracy of risk assessments of the compounds. In this study, a selective and sensitive analytical method was established to simultaneously determine 19 natural and 42 synthetic progestins in environmental waters, and the synthetic progestins included 19-nortestosterone, 17α-hydroxyprogesterone and progesterone derivatives. All of the target compounds were effectively separated using an HSS T3 column, and the recoveries for effluent and river samples were 80–115% and 75–105%, respectively. The detection limits for the 61 analytes were in the range of 0.05–0.60 ng/L and 0.03–0.40 ng/L for the effluent and river samples, respectively. The developed method is applied to analyze the target progestogens in sewage effluent and river water samples from Beijing. The detected concentrations of natural progesterone metabolites (3α-hydroxy-5β-tetrahydroprogesterone) were up to 63 times higher than those of the parent compound. Of the three groups of synthetic progestins, the progesterone derivatives were detected for the first time and had the highest concentrations followed by the 19-nortestosterone and 17α-hydroxyprogesterone derivatives. In contrast to previous studies, the predominant derivative compounds of 19-nortestosterone were found to be 19-nortestosterone, gestodene and mifepristone, and those of 17α-hydroxyprogesterone were 6-epi-medroxy progesterone 17-acetate and melengestrol acetate. The toxicities and environmental risk of these emerging progestins deserves more attention in the future.

Oral Allylestrenol: A Pregnancy-supporting Progestogen

ABSTRACT Allylestrenol is a synthetic progestogen that has been in therapeutic use in the management of mild to severe cases of certain obstetric complications, like selected forms of miscarriage/abortion, threatened preterm labor, intrauterine growth restriction (IUGR), and gestational hypertension. Natural progesterone may be used for treatment; however, it has the property of being rapidly metabolized in the liver besides having little or no oral activity. While there are many other synthetic and orally administrable progesterone analogs in the market, most of them, which are 19-nortestosterone derivatives, possess various undesirable side effects like symptoms of intolerance and a tendency to virilization. Allylestrenol, despite being a 19-nortestosterone derivative, has no known side effects including those attributed to the other members of its class, which is theorized to be due to subtle differences in its chemical structure, giving it a unique mechanism of action consisting of a triple effect—trophoblastic, placentotropic, and β2-adrenergic. The present review is mainly aimed at understanding the whys and wherefores behind the molecule's moderate efficacy and remarkable safety along with examining the data from various studies. How to cite this article Malhotra N, Garg R, Malhotra N, Malhotra J. Oral Allylestrenol: A Pregnancy-supporting Progestogen. J South Asian Feder Obst Gynae 2017;9(4):297-303.

Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF).

To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion. Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos. Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase. A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient.

Combined therapy of extensive genital endometriosis with aromatase inhibitors

The article represents our experience in evaluation of aromatase activity in endometriotic lesions. We revealed that the most important parameter in evaluating aromatase activity is the area of its expression. Increased activity of this enzyme in the foci of endometriosis was identified, which proved the prescription of aromatase inhibitors in postoperative period for 68 patients of reproductive age with genital endometriosis. It was shown that the combined therapy of endometriosis-aromatase inhibitors and progestagens (19-nortestosterone derivatives) is effective, safe and well tolerated way of treatment of the disease, but, undoubtedly, this scheme requires further research

Bimodal binding and free energy of the progesterone receptor in the induction of female sexual receptivity by progesterone and synthetic progestins

Synthetic progestins (SPs) are used for regulation of fertility, contraception and hormone replacement therapy. The acetylated medroxyprogesterone (MPA), megestrol (MGA) and chlormadinone (CLA) are related to progesterone (P). Other SPs are 19-nortestosterone derivatives such as: norethisterone (NET), norethynodrel (NED) or the 13-ethyl gonane, levonorgestrel (LNG). We studied MPA, NET, NED and LNG in a dose–response manner to induce sexual receptivity in rats. Results showed that MPA, NET and NED act as partial agonists, with similar or lower potency than P. However, LNG is a full agonist. Additionally, the molecules of MPA, MGA, CLA, NET, NED, LNG, and P, were submitted to computer calculations at ab initio quantum mechanics theory, to obtain their electronic structure and molecular properties. The aim was to correlate their behavioral effect with their physicochemical properties. In addition, the crystals of P, NET and LNG bound to the progesterone receptor (PR) were studied. The PR crystallizes as a dimer forming two monomers (mA and mB), in which Gln725 interacts in either of two possible ways with the C3-carbonyl pharmacophore of progestins. P binds differentially to both PR monomers, while NET binds exclusively as mA and LNG binds only as mB in both monomers with no difference. Energetically, binding of LNG and P to mB, is more favorable than that of NET and P to mA. Consequently, this bimodal mechanism increases the action possibilities of SPs on biological systems. Interestingly, progestin potency depends mostly on local molecular structure and electronic features, prevailing over total molecular properties.

Comparison of 7α-methyl-19-nortestosterone effectiveness alone or combined with progestins on androgen receptor mediated-transactivation

7α-methyl-19-nortestosterone (MENT) is an androgen with potent gonadotropin inhibitory activity and prostate-sparing effects. These attributes give MENT advantages over testosterone as a male contraceptive, but, as in the case of testosterone, a partial dose-dependent suppression of spermatogenesis has been observed. Combination of testosterone or MENT with synthetic progestins improves the rate of azoospermia; however, it is unknown whether these combinations affect hormone androgenicity or exert synergistic effects via progestational or androgenic interaction. Herein, using transactivation assays, we examined the ability of MENT alone or combined with several 19-nor-derived synthetic progestins to activate androgen receptor (AR)-dependent gene transcription. In addition, the capability of 7α-methyl-estradiol (7α-methyl-E(2)), an aromatized metabolite of MENT, to transactivate gene transcription via estrogen receptor α (ERα; ESR1) or ERβ (ESR2) was also investigated. As expected, MENT induced gene transactivation through either the progesterone receptor (PGR) or the AR. MENT was as efficient as progesterone in activating PGR-mediated reporter gene expression, but it was ten times more potent than testosterone and dihydrotestoterone in activating of AR-driven gene expression. The addition of increasing concentrations of other 19-nortestosterone derivatives (norethisterone or levonorgestrel) did not affect, in a significant manner, the ability of MENT to activate AR-dependent reporter gene transcription. The same results were obtained with different cell lines. 7α-Methyl-E(2) resulted in potent estrogen activity via both ER subtypes with efficiency similar to natural E(2). These results suggest that the addition of 19-nortestosterone-derived progestins, as a hormonal adjuvant in male fertility strategies for effective spermatogenic suppression, does not display any detrimental effect that would interfere with MENT androgenic transcriptional activity.

Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3

The human aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are important 20-ketosteroid reductases in pre-receptor regulation of progesterone action. Both AKR1C1 and AKR1C3 convert progesterone to the less potent metabolite 20α-hydroxyprogesterone, although AKR1C1 has a higher catalytic efficiency than AKR1C3. Recently, we reported significant up-regulation of AKR1C1 and AKR1C3 in ovarian endometriosis, a complex estrogen-dependent disease. The typical characteristics of endometriosis are increased formation of estradiol, which stimulates proliferation of endometriotic tissue, and disturbed action of the protective progesterone. Although progestins have been used for treatment of endometriosis since the 1960s, their detailed mechanisms of action are still not completely understood. In the present study, we evaluated the potential inhibitory effects of progestins on the pre-receptor regulatory enzymes AKR1C1 and AKR1C3. We examined the following progestins as inhibitors of progesterone reduction catalyzed by recombinant AKR1C1 and AKR1C3: progesterone derivatives (dydrogesterone, its metabolite, 20α-hydroxydydrogesterone; and medroxyprogesterone acetate), 19-nortestosterone derivatives (desogestrel, norethinodrone and levonorgestrel), and the androgen danazol. Dydrogesterone, medroxyprogesterone acetate, 20α-hydroxydydrogesterone and norethinodrone inhibited AKR1C1 and AKR1C3 with K i values of 1.9 μM, 7.9 μM, 20.8 μM and 48.0 μM, and of 0.5 μM, 1.4 μM, 18.2 μM and 6.6 μM, respectively. Levonorgestrel and desogestrel preferentially inhibited AKR1C3 with K i values of 5.6 μM and 39.1 μM, respectively. Our data thus show that dydrogesterone, medroxyprogesterone acetate, 20α-hydroxydydrogesterone and norethinodrone inhibit AKR1C1 and AKR1C3 in vitro, although their physiological inhibitory effects still need to be evaluated further. Additionally, we investigated whether progestin dydrogesterone can be metabolized to its active 20α-hydroxymetabolite by AKR1C1 and AKR1C3. AKR1C1 converted dydrogesterone with a high catalytic efficiency while AKR1C3 was less active, which suggests that in vivo dydrogesterone is metabolized mainly by AKR1C1. Docking simulations of dydrogesterone into AKR1C1 and AKR1C3 also support these experimental data.

Norethisterone-induced hepatic adenomas can cause life-threatening bleeding in girls with inherited platelet disorders

To describe four cases of hepatic adenoma in adolescents and women with severe inherited bleeding disorders treated with norethisterone. Case reports. Necker-Enfants Malades University Hospital, Paris, Department of Pediatric Endocrinology, Gynecology and Diabetes. Two adolescents and two young women with inherited platelet disorders, treated with high-dose norethisterone (10 to 20 mg/day) to induce amenorrhea. Immediate cessation of norethisterone. Spontaneous regression of hepatic adenoma. In four patients with inherited platelet disorders, hepatic adenoma developed at 14, 18, 22, and 24 years of age, respectively, during continuous norethisterone therapy started at 1.5, 2.5, 10.0, and 13.0 years of age, respectively. Life-threatening bleeding occurred in two patients. Immediate norethisterone discontinuation was followed by complete or nearly complete tumor regression within a few months. Our four cases strongly support a causal link between norethisterone treatment and hepatic adenoma. Continuous high-dose (10 to 20 mg/day) continuous norethisterone to treat menorrhagia in adolescents and young women with bleeding disorders is inadvisable. If other nortestosterone derivatives are needed, the patient should be closely monitored for the development of hepatic adenoma.

Ligand-induced large-scale chromatin dynamics as a biosensor for the detection of estrogen receptor subtype selective ligands

Estrogen receptors (ER), members of the nuclear steroid receptor superfamily, act to activate transcription through ligand-dependent recruitment of coregulators and chromatin modifications. A series of synthetic A-ring reduced 19-nortestosterone-derived progestins has the capacity to selectively bind ERα for activated transcription, and to recruit coregulatory factors. In this study, we have analyzed the ability of synthetic 19-nortestosterone derivatives to visibly alter the configuration of ER-target gene chromatin using a novel mammalian promoter transcriptional biosensor (PRL-array) stably transfected into the genome of HeLa cells (PRL-HeLa cells). Results from synthetic steroid-treated cells expressing functional GFP-ERα or YFP-ERβ chimeras were compared to those obtained with estradiol (E 2) and the antiestrogen tamoxifen. In the presence of synthetic ligands or E 2 a concentration-dependent increase in area of the biosensor array was observed in GFP-ERα-expressing PRL-HeLa cells. No significant differences were found between the effects obtained with natural and synthetic steroids. Similarly, E 2 or synthetic steroids-treated PRL-HeLa cells also resulted in similar colocalization of SRC-1- and RNAPII-immunofluorescence at the array. YFP-ERβ-expressing PRL-HeLa cells treated with E 2 showed increases in array area that were similar to ERα; however, treatment of YFP-ERβ-expressing cells with synthetic ligands was indistinguishable from vehicle controls. These data indicate that A-ring reduced 19-nortestosterone derivatives have an estrogen-like effect on chromatin, including recruitment of transcription factors through selective interactions with ERα.

Nomegestrol Acetate

This review summarizes the pharmacology, safety and clinical efficacy of nomegestrol acetate, based on the available published literature, and assesses the pharmacological characteristics that underlie a role in different gynaecological disorders and hormone replacement therapy (HRT), and a potential role in combination estrogen/progestogen oral contraception. Nomegestrol acetate is a potent, orally active progestogen with a favourable tolerability profile and neutral metabolic characteristics. Unlike the majority of older progestogens, which were 19-nortestosterone derivatives synthesized primarily for their antigonadotropic activity as a component of hormonal contraception in combination with an estrogen, nomegestrol acetate is a 19-norprogesterone derivative designed to bind specifically to the progesterone receptor, and is relatively lacking in affinity for other steroid receptors. Nomegestrol acetate exerts strong antiestrogenic effects at the level of the endometrium and has potent antigonadotropic activity, but without any residual androgenic or glucocorticoid properties. At a dosage of 1.25 mg/day, nomegestrol acetate inhibits ovulation while permitting follicle growth, whereas at dosages of 2.5 or 5 mg/day, both ovulation and follicle development are suppressed. The antigonadotropic action of nomegestrol acetate is mediated, like other progestins, at the hypothalamic and pituitary level. Moreover, nomegestrol acetate has partial antiandrogenic activity. Absorption of nomegestrol acetate is rapid after oral administration, reaching a peak serum concentration within 4 hours, with a terminal half-life of approximately 50 hours. Nomegestrol acetate has been used successfully for the treatment of some gynaecological disorders (menstrual disturbances, dysmenorrhoea, premenstrual syndrome) and as a component of HRT in combination with estradiol for the relief of menopausal symptoms; it has been approved in Europe as monotherapy for the treatment of the menopausal syndrome, uterine diseases and menorrhagia, and in combination with an estrogen for the treatment of menopausal symptoms. In vitro data suggest that nomegestrol acetate preserves the beneficial haemostatic effects of estrogen; furthermore, nomegestrol acetate has a neutral or beneficial effect on lipid profiles, and does not adversely affect glucose metabolism or bodyweight. Nomegestrol acetate has shown a lack of profilerative activity in normal and cancerous breast tissue, and does not have a deleterious effect on bone remodelling. These potent antigonadotropic properties, and other beneficial metabolic and pharmacological characteristics, suggest that nomegestrol acetate can be an effective progestogen for use in combination with an estrogen in oral estrogen/progestogen contraceptive treatment and in HRT, while it also provides some non-contraceptive benefits for women's health.

Dienogest: A New Therapeutic Agent for the Treatment of Endometriosis

Dienogest (DNG), a progestin of 19-nortestosterone derivative, has good oral bioavailability and is highly selective for progesterone receptors. Owing to its antiovulatory, antiproliferative activities in endometrial cells, and its inhibitory effects on the secretion of cytokines, DNG is expected to be an effective treatment for endometriosis. Progesterone receptor-binding affinity is higher for DNG than for progesterone. Several pilot studies demonstrated that after 24 weeks of DNG treatment, there was a significant decrease in terms of dysmenorrhea, premenstrual pain, dyspareunia and diffuse pelvic pain. Most of the cases of genital bleeding occurring in the DNG treatment were spotting or breakthrough bleeding, which decreased with continued treatment and resolved either during treatment or after the end of treatment. The therapeutic effects of DNG 2 mg/day and norethisterone acetate 10 mg/day for endometriotic symptoms during a period of 24 weeks were almost similar. The only disadvantage of DNG seems to be the irregular bleeding. Good efficacy and tolerability of DNG in patients with endometriosis have been demonstrated in an open, randomized European clinical trial as compared with norethisterone acetate. In Japan, a Phase III, randomized, double-blind, multicenter, controlled trial was conducted to compare the efficacy and safety of DNG with intranasal buserelin acetate in patients with endometriosis. The study demonstrated that DNG is as effective as intranasal buserelin acetate in alleviating endometriosis symptoms, and causes less bone mineral density loss, resulting in the use on a commercial basis for endometriosis patients in Japan from 2008. This paper provides summarized data on this new promising drug for endometriosis.

The synthetic approach to STS 557 - structure activity relationships in 17 alpha-CH2X-substituted 19-nortestosterone derivatives.

The synthesis of 17 alpha-CH2X-substituted 19-nortestosterone derivatives (X = halogen, CN, N3, OH, NH2 etc.) is described. Starting with 1,4-dihydroestradiol 3-methyl ether the 17 alpha-CH2X-17 beta-hydroxy-moiety was introduced via a 17 beta-spiroepoxide which could be cleaved with various nucleophilic agents giving the desired derivatives. In the McPhail assay with immature rabbits some of these substances showed good progestagenic activity on oral administration. The influence of structural modifications on the activity is discussed. The best effect is observed if an additional double bond is introduced in position 9(10). While the 19-nortestosterone derivative with X = CN has only an activity of about 20% of that of norethisterone acetate, the introduction of a second double bond leads to a compound (STS 557) which has an oral potency more than ten times as high as levonorgestrel.

Reprint of Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several newprogestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17α-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.